Process for the preparation of substituted halogenated aniline

ABSTRACT

A process for the preparation of substituted halogenated anilines from substituted halogenated 1-chlorobenzenes which comprises a) reacting a substituted halogenated 1-chlorobenzene selectively with an imine in the presence of a transition metal catalyst complex and a base to form an N-aryl imine; b) hydrolyzing the N-aryl imine; and c) isolating the substituted halogenated aniline.

CROSS REFERENCE TO RELATED APPLICATION

This application is a 35 USC § 371 National Phase Entry Application fromPCT/EP2003/014354, filed Dec. 16, 2003, and designating the UnitedStates, which claims the benefit of Provisional Application No.60/433,847 filed Dec. 16, 2002.

This invention relates to a method for the preparation of substitutedhalogenated anilines from substituted halogenated 1-chlorobenzenes,especially to substituted fluoroanilines from substituted1-chlorofluorobenzenes.

For Example 3,5-difluoroaniline is used in the synthesis of importantagricultural compounds such as diflufenzopyr. The currently availablesynthetic procedures for 3,5-difluoroaniline are expensive andcorrosive. One synthesis uses the expensive 2,4-difluoroaniline as astarting material. Other synthetic routes are also high cost becausethey either involve expensive reagents or have low yields. As a resultthere is a need for a more economic commercial process to produce thisintermediate.

This invention relates to a method for the preparation of substitutedhalogenated anilines from substituted halogenated chlorobenzenes,especially substituted fluoroanilines from substituted1-chlorofluorobenzenes in high yield. The substituted halogenatedanilines are prepared by selectively reacting the chlorine of thesubstituted halogenated 1-chlorobenzene and an imine in the presence ofa transition metal catalyst complex to form an N-aryl imine that is thentransformed with or without isolation to the corresponding primaryamine.

The process of the instant invention can be represented by thegeneralized reaction depicted in Scheme I.

wherein

-   R¹ is halogen, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₁–C₆ alkoxy, C₃–C₆    cycloalkyl, C₃–C₆ cycloalkyl C₁–C₆alkyl or aryl;-   R², R³ are aryl;-   Hal is fluorine or chlorine;-   m is 1 or 2; and-   n is 1 or 2.

Suitable transition metal catalysts include soluble or insolublecomplexes of platinum, palladium and nickel. Nickel and palladium areparticularly preferred and palladium is most preferred. The metal centerof palladium catalysts Is desirably in the zero-valent state or iscapable of being reduced to metal (0). Suitable soluble palladiumcomplexes include, but are not limited to, tris(dibenzylideneacetone)dipalladium [Pd₂(dba)₃], bis(dibenzylideneacetone) dipalladium[Pd(dba)₂] and palladium acetate.

Catalyst complexes may comprise chelating ligands, like alkyl and arylderivatives of phosphines and bisphosphines, imines, arsines, andhybrids thereof, including hybrids of phosphines with amines. Thephosphines can be monodentate phosphine ligands, liketrimethylphosphine, triethylphosphine, tripropylphosphine,triisopropylphosphine, tributylphosphine, tricyclohexylphosphine,trimethylphosphite, trethyl phosphite, tripropyl phosphite,triisopropylphosphite, tributyl phosphite and tricyclohexylp phosphite,in particular triphenylphosphine, tri(o-toyl)phosphine,triisopropylphosphine or tricyclohexylphosphine; or a bidentatephosphine ligand such as 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(BINAP), 1,2-bis(dimethylphosphino)ethane,1,2-bis(diethylphosphino)ethane, 1,2-bis(dipropylphosphino)ethane,4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xant-phos),1,1′-bis(diphenylphosphino)ferrocene (dppf),bis(2-(diphenylphosphino)phenyl)ether [DPE-phos],1,2-bis(diisopropylphosphino)ethane, 1,2-bis(dibutylphosphino)ethane,1,2-bis(dicyclohexylphosphino)ethane,1,3-bis(diisopropylphosphino)propane,1,3-bis(dicyclohexylphosphino)propane,1,4-bis(diisopropylphosphino)butane,1,4-bis(dicyclohexylphosphino)butane, 1,4-bis(diphenylphosphino)butane(bppb) and 2,4-bis(dicyclohexylphosphino)pentane. Also ligandscomprising Lewis basic nitrogen atoms may be included in the transitionmetal catalyst, e.g. 1,10-phenanthroline and the like. Preferred are1,10-phenanthroline and the like. Preferred are1,1′-bis(diphenylphosphino)ferrocene (dppf) and1,4-bis(diphenylphosphino)butane (bppb).

Suitable bases are selected from the group consisting of alkoxides,carbonates, bicarbonates, hydroxides, amides, amines, phosphates andfluorides. Especially the base is selected from an alkoxide such assodium tert-butoxide, potassium tert-butoxide, sodium methoxide; analkali metal amide such as sodium amide, lithium diisopropylamide or analkali metal bis(trialkylsilyl)amide such as lithiumbis-(trimethyl-silyl)amide or sodium bis-(trimethyl-silyl)amide, atertiary amine such as triethylamine, trimethylamine,N,N-dimethylaminopyridine, 1,5-diazabicycl[4.3.0]nonene-5 (DBN),1,5-diazabicycl-[5.4.0]undecene-5 (DBU) as well as an alkali, alkalineearth carbonate, bicarbonate or hydroxide such as sodium, magnesium,calcium, barium, potassium, or cesium carbonate, hydroxide orbicarbonate. Preferred is sodium tert-butoxide.

The acid used to cleave the imine is preferably an aqueous inorganicacid such as hydrochloric acid, or sulphuric acid.

Alternatively, the reaction to cleave the N-aryl imine and form thedesired aniline is carried out by other procedures known in the art.

In a preferred embodiment the radical R¹ of the substituted halogenatedanilines is halogen, like fluorine or chlorine, C₁–C₆ alkyl, like methylor ethyl or C₂–C₆ alkenyl, like vinyl or allyl; especially R¹ ishalogen, like fluorine or chlorine, or C₁–C₆ alkyl, like methyl;preferably R¹ is fluorine, chlorine or methyl.

In another preferred embodiment the radicals R² and R³ of thesubstituted halogenated anilines are phenyl or naphthyl, especiallyphenyl.

In another preferred embodiment m is 1 and n is 1 or 2.

In another preferred embodiment Hal is linked in meta position to thephenyl moiety (with regard to the amino group) and m is 1.

In another preferred embodiment the base used in the first step of thereaction is preferably an alkali or earth alkaline alkoxide or an alkalior earth alkaline carbonate, most preferably sodium tert-butoxide.

In another preferred embodiment the N-aryl imine is isolated andpurified.

In another preferred embodiment the N-aryl imine is reacted in thesecond step without isolation or purification.

The term “aryl” refers to a group that contains one or more aromaticrings, for example, phenyl or naphthyl, which are unsubsituted orpartially or fully halogenated and/or may carry one to three of thefollowing radicals: nitro, cyano, C₁–C₄ alkyl, C₁–C₄ haloalkyl, C₁–C₄alkoxy or C₁–C₄ haloalkoxy. In a preferred embodiment “aryl” refers tophenyl.

The reaction is generally carried out in an inert solvent, preferablyone in which the reaction ingredients, including the catalyst, aresubstantially soluble. Suitable solvents include ethers such as diethylether, 1,2-dimethoxy ethane, diglyme, t-butyl methyl ether,tetrahydrofuran, and the like, aliphatic or aromatic hydrocarbonsolvents such as benzene, xylene, toluene, hexane, pentane and the like,esters and ketones such as ethyl acetate, acetone and 2-butanone; polaraprotic solvents such as aceotnitrile, di-methylsulfoxide,dimethylformamide and the like; or combinations of two or more solvents.

The reaction is typically carried out in the temperature range of fromabout 25° C. to about 300° C., more preferably in the range of fromabout 25° C. to about 150° C.

In certain embodiments it is preferable to perform the reactions underan inert atmosphere of a gas such as nitrogen or argon, preferablynitrogen.

In a preferred embodiment Hal and R¹ are both chlorine or fluorine;especially m and n are both 1; in particular these radicals are linkedin meta/meta′ position to the phenyl moiety (with regard to the aminogroup).

In another preferred embodiment Hal is chlorine or fluorine and R¹ isC₁–C₆ alkyl, especially methyl; especially m and n are both 1;preferably Hal is linked in meta position to the phenyl moiety (withregard to the amino group); in particular R¹ is linked in ortho positionto the phenyl moiety (with regard to the amino group).

In another preferred embodiment the imine is benzophenone imine.

In another preferred embodiment, this invention relates to a method forthe preparation of 3,5-difluoroaniline from1-chloro-3,5-difluorobenzene. More particularly the invention comprisesreacting 1-chloro-3,5-difluorobenzene with benzophenone imine in thepresence of a palladium catalyst and a ligand such as1,1′-bis(diphenylphosphino)ferrocene (dppf) or1,4-bis-diphenylphosphinobutane (dppb) to form an intermediate iminewhich is then reacted, without isolation or purification, with acid toobtain the desired 3,5-difluoroaniline.

In another preferred embodiment, this invention relates to a method forthe preparation of 3,5-dichloroaniline from 1,3,5-trichlorobenzene. Moreparticularly the invention comprises reacting 1,3,5-trichlorobenzenewith benzophenone imine in the presence of a palladium catalyst and aligand such as 1,1′-bis(diphenylphosphino)ferrocene (dppf) or1,4-bis-diphenylphosphinobutane (dppb) to form an intermediate iminewhich is then reacted, without isolation or purification, with acid toobtain the desired 3,5-dichloroaniline.

In another preferred embodiment, this invention relates to a method forthe preparation of 3-chloro-2-methylaniline from 2,6-dichlorotoluene.More particularly the invention comprises reacting 2,6-dichlorotoluenewith benzophenone imine in the presence of a palladium catalyst and aligand such as 1,1′-bis(diphenylphosphino)ferrocene (dppf) or1,4-bis-diphenylphosphinobutane (dppb) to form an intermediate iminewhich is then reacted, without isolation or purification, with acid toobtain the desired 3-chloro-2-methylaniline.

EXAMPLE 1 3,5-Difluoroaniline

A 4-neck, 500 mL flask was equipped with a mechanical stirrer, a glassstopper, a rubber septum and a condenser with an inert gas inlet. Tothis flask was added, in order, tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃) (25 mg, 0.01 mol %),1,1′-bis(diphenylphosphino)ferrocene (dppf) (46 mg, 0.03 mol %), sodiumtert-butoxide (37 g, 1.4 eq, xylenes (90 mL),1-chloro-3,5-difluorobenzene (49.2 g, 0.33 mol) and benzophenone imine(50 g, 0.28 mol). The mixture was refluxed for 8 hours until GC analysisconfirmed that the benzophenone imine had been consumed. The reactionmixture was cooled slightly, and 150 mL of 2M HCl was added slowly tothe reaction mixture with some gas evolution and the mixture wasrefluxed with sufficient agitation for 45 minutes. While still warm, thereaction mixture was put in a separatory funnel and the aqueous layerwas collected. An additional 90 mL of xylenes was added to theseparatory funnel and the organic layer was washed with 4×100 mL 1M HCl.The acidic fractions were combined and made alkaline with aqueous concammonium hydroxide. The free amine was extracted with 250 mL methyltert-butyl ether. The organic layer was dried over magnesium sulfate andconcentrated in vacuo to yield the expected product in 89% yield.

EXAMPLE 2 3,5-dichloroaniline

A 50 mL 3 neck round bottom flask was oven dried, cooled under nitrogen,and charged with 14.50 g of xylenes. The flask was then charged with1,3,5-trichlorobenzene (9.760 g, 53.49 mmol), benzophenone imine (7.620g, 42.04 mmol), (dba)₃Pd₂ catalyst (0.023 g, 0.03 mmol in 2 g xylene),dppf ligand (0.042 g, 0.08 mmol in 2.g xylene) and sodium t-butoxide(5.550 g, 57.70 mmol). The reaction mixture was heated to reflux (136°C.) for 3 hours and then cooled to room temperature. The aromatic imineintermediate was then hydrolyzed with 22 mL of 2 N HCl (aq) at 70° C.for 45 minutes. The hydrochloride salt of dichloroaniline precipitatedout of solution when cooled to room temperature. The crude hydrochloridesalt was collected by filtration using a buchner funnel and then washedwith methyl-tert. butyl ether. The dichloroanaline salt was then addedto 30 mL of methyl-tert. butyl ether and pH adjusted to 12 using 50%NaOH. The methyl-tert. butyl ether phase was collected and then strippedunder vacuum to give 3,5-dichloroaniline in 86% yield.

EXAMPLE 3 3-chloro-2-methylanaline

A 50 mL 3 neck round bottom flask was oven dried, cooled under nitrogen,and charged with 18.6 grams of xylenes. The flask was then charged with2,6-dichlorotoluene (7.995 g, 49.65 mmol), benzophenone imine (7.612 g,42.0 mmol), (dba)₃Pd₂ catalyst (0.023 g, 0.025 mmol in 2.27 g xylene),dppf ligand (0.042 g, 0.08 mmol in 2.53 g xylene) and sodium t-butoxide(5.689 g, 59.19 mmol). The reaction was heated to 125 ° C. for 6 hrs andthen cooled to room temperature. The aromatic imine intermediate washydrolyzed with 2 N HCl (aq) at 65° C., cooled to room temperature, andthen transferred to a separatory funnel. The aqueous phase was collectedand the organic phase was extracted 2 more times with 2 N HCl. Theaqueous phases were then combined with 20 mL of methyl tert.-butyl etherand treated with 50% NaOH (aq) to pH of 11. The aqueous phase was thenextracted 2 more times with 20 mL of methyl tert.-butyl ether. Themethyl tert.-butyl ether phases were combined and stripped understripped under vacuum to give 3-choro-2-methylanalaline in 75.5% yieldin a purity of 97.7% GC-MS.

1. A process for the preparation of a substituted halogenated1-chlorobenzene, the process comprising (a) reacting a substitutedhalogenated 1-chlorobenzene with an imine in the presence of atransition metal catalyst and a base to form an n-aryl imine; and (b)hydrolyzing the N-aryl imine to form a substituted halogenated aniline.2. The process of claim 1 wherein the substituted halogenated1-chlorobenzenes has the structure

wherein R¹ is halogen, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₁–C₆ alkoxy, C₃–C₆cycloalkyl, C₃–C₆ cycloalkyl C₁–C₆alkyl or aryl; Hal is fluorine orchlorine; m is 1 or 2; and n is 1 or
 2. 3. The process of claim 2wherein the imine has the structure

wherein R², R³ are independently aryl.
 4. The process of claim 2,wherein R¹ is halogen or C₁–C₆-alkyl; m is 1; n is 1 or
 2. 5. Theprocess of claim 2, wherein the substituted halogenated 1-chlorobenzenesis 1-chloro-3,5-difluorobenzene.
 6. The process of claim 2, wherein thesubstituted halogenated 1-chlorobenzenes is 1,3,5-trichlorobenzene. 7.The process of claim 2, wherein the substituted halogenated1-chlorobenzenes is 2,6-dichlorotoluene.
 8. The process of claim 1,wherein the base is an alkoxide salt.
 9. The process of claim 8 whereinthe alkoxide salt is sodium tert-butoxide.
 10. The process of claim 1,wherein the transition metal catalyst complex is a platinum, palladiumor nickel complex.
 11. The process of claim 10, wherein the transitionmetal catalyst complex comprises a chelating ligand.
 12. The process ofclaim 10, wherein the chelating ligand is a alkyl or aryl derivative ofa phosphine or bisphosphine.
 13. The process of claim 11, wherein thetransition metal catalyst complex is Pd₂(dba)₃/dppf or Pd₂(dba)₃/dppb.14. The process of claim 13, wherein the transition metal catalystcomplex is Pd₂(dba)₃/dppf.
 15. The process of claim 13, wherein thetransition metal catalyst complex is Pd₂(dba)₃/dppb.
 16. The process ofclaim 1, including the further step of isolating the substitutedhalogenated aniline.
 17. A process for the preparation of3,5-difluoroaniline comprising: a) reacting 1-chloro-3,5-difluorobenzenewith benzophenone in the presence of a palladium catalyst complex whichcomprises 1,1′-bis(diphenylphosphino) ferrocene (dppf) or1,4-bis-diphenylphosphinobutane (dppb) to form an intermediate imine;and (b) hydrolyzing with acid the intermediate imine to form3,5-difluoroanline.
 18. A method for the preparation of3,5-dichloroaniline comprising: a) reacting 1,3,5-trichlorobenzene withbenzophenone imine in the presence of a palladium catalyst complex whichcomprises 1,1-bis(diphenylphosphino) ferrocene (dppf) or1,4-bis-diphenylphosphinobutane (dppb) to form an intermediate imine:and (b) hydrolyzing with acid the intermediate imine to form3,5-dichloroaniline.
 19. A process for the preparation of3-chloro-2-methylaniline comprising; (a) reacting 2,6-dichlorotoluenewith benzophenone imine in the presence of a palladium catalyst complexwhich comprises 1,1′-bis(diphenylphosphino) ferrocene (dppf) or1,4-bis-diphenylphosphinobutane (dppb) for form an intermediate imine;and (b) hydrolyzing with acid the intermediate imine to form3-chloro-2-methylaniline.